Glutamate-induced excitotoxicity and oxidative stress are mechanisms implicated in the pathogenesis of Alzheimer's disease (AD). We found that ephrinB ligands (ephrinBLs) protect primary neuronal cultures from glutamate- and oxidative stress-induced toxicity and that the neuroprotective activities of ephrinBLs depend on EphB receptors (EphBRs) and presenilini (PS1), a protein involved in familial AD (FAD). We also observed that PS1 mediates the neuroprotective effects of brain-derived neurotrophic factor (BDNF). Interestingly, the neuroprotective activities of ephrinBLs and BDNF depend on both alleles of PS1 because absence of either one or both alleles results in the inhibition of trophic factor-induced neuroprotection. Furthermore, the neuroptotective activities of ephrinBLs and BDNF are significantly reduced in neurons either heterozygous or homozygous for FAD mutants of PS1. In contrast, the neuroprotective function of basic fibroblast growth factor (bFGF) is affected neither by WT nor by mutant PSl Our data suggest a novel mechanism of neurodegeneration in FAD where brain neurons expressing FAD mutants of PS1 may have reduced ability to respond to neuroprotective factors and therefore are more vulnerable to toxic insults then wild type neurons. This decreased neuroprotection may result in increased rates of neuronal loss and over many years, in severe depletion of neuronal populations. Here we propose tp investigate further the effects of PS1 and its FAD mutants oh the neuroprotective function of trophic factors in vitro using primary neuronal cultures and in vivo using PS1 knockout and FAD knock-in mouse models. We will use the same technology we employed for PS1 to explore the neuroprotective activities of presenilin 2 (PS2) and the amyloid precursor protein (APP). In addition, we will explore mechanisms involved in the neuroprotective function of PS1 including the role of MP/y-secretase receptor processing and endocytosis in the neuroprotecive activities of PS1, BDNF and ephrinBLs and the effects of PS1 and FAD mutants on ligand-induced receptor phosphorylation and downstream signaling. RELEVANCE (See instructions): Excitotoxicity and oxidative stress are implicated in neurodegeneration and Alzheimer disease (AD). We found that PSl, a protein involved in familial AD, mediates the neuroprotective functions of brain factors like ephrinB and BDNF. These factors are unable to protect neurons in the absence of PS1. Interestingly, genetic changes that promote AD interfere with the neuroprotective function of PS1. Our findings have implications for the mechanism of neurodegeneration and mav provide novel targets for therapeutic intervention in AD.